After brief periods of heightened stimulation, calcium entry through L-type calcium channels leads to activation of the transcription factor cAMP response element-binding protein (CREB) and CRE-dependent transcription. Many of the details surrounding the mechanism by which L-type calcium channels are privileged in signaling to CREB, to the exclusion of other calcium entry pathways, has remained unclear. We hypothesized that the PDZ interaction sequence contained within the last four amino acids of the calcium channel

Fig. 3. Qualitative consistency of CaM translocation after depolarization in various neuronal populations. (A)After a 3-min, 90-mM K ϩ stimulation, significant increases in CREB phosphorylation were observed in hippocampal neurons taken from region CA3-CA1 (P Ͻ 0.001) or dentate gyrus (DG) (P Ͻ 0.001). (B and C) In granule cells from the dentate gyrus (DG), significant increases in nuclear CaM also were observed (P Ͻ 0.05), although the changes were less pronounced than in CA3-CA1 cells (P Ͻ 0.001). (D) Increased nuclear CaM in cerebellar granule cells (Cereb) (P Ͻ 0.001), similar in magnitude to that observed in CA3-CA1 pyramidal neurons. The neuronal nucleus plays a vital role in information processing, but whether it supports computational functions such as paired-pulse facilitation, comparable to synapses, is unclear. Ca 2؉ -dependent movement of calmodulin (CaM) to the nucleus is highly responsive to Ca 2؉ entry through L-type channels and promotes activation of the transcription factor CREB (cAMPresponsive element binding protein) through phosphorylation by CaM-sensitive kinases. We characterized key features of this CaM translocation and its possible role in facilitation of nuclear signaling. Nuclear CaM was elevated within 15 s of stimulus onset, preceding the first signs of CREB phosphorylation in hippocampal pyramidal neurons. Depolarization-induced elevation of nuclear CaM also was observed in cerebellar granule cells, neocortical neurons, and dentate gyrus granule cells. 4132-4133